The invention relates to a pharmaceutical in which a first pharmacologically active substance, or a pharmaceutically acceptable salt thereof, which acts on a specific biological function, is integrated such therein that it is released according to a predetermined first release profile (D.1), which generates a first activity profile (I.1) with at least one flank of increasing and at least one flank of decreasing activity intensity, especially a set forth below, processes for the manufacture thereof and to methods of treatment comprising administering such a pharmaceutical.
Pharmaceuticals contain at least one pharmacologically active substance which, after administration of the pharmaceutical to a human or an animal, is to act via biological-chemical pathways in regard to at least one biological function of the human or animal, wherein the activity may be of a therapeutic or prophylactic nature or desired for other reasons. In many cases, the requirements placed on the pharmaceutical not only relate to a specific type of action but also a specific temporal course of the activity intensity, i.e., a specific activity profile.
The activity profile of an administered pharmacologically active substance is not directly measurable in many cases. However, based on medical experience and optionally with the aid of the temporal course of the corresponding blood level, the activity profile can be deduced for large groups of pharmacologically active substances and for different administration methods with sufficient reliability.
The type of action as well as the activity profile of a pharmaceutical, respectively, of a pharmacologically active substance contained in the pharmaceutical depend on pharmacodynamic parameters which determine the effect of the active substance on the organism (in particular, dosage and responsiveness) and on the pharmacokinetic parameters which determine the effect of the organism on the active substance (in particular, resorption, distribution, and storage in the organism as well as elimination by excretion or metabolism). It is attempted in many different ways to produce pharmaceuticals by which not only a pharmacologically active substance is administered to the organism but by which also additionally at least some of the above-mentioned parameters can be affected such that an activity profile that is as optimal as possible for the application is achieved with a dosage that is as minimal as possible.
For generating an activity profile as advantageous as possible, the pharmacologically active substance is administered according to a selected administration profile (administration dosage as a function of time), in a selected form (for example, lipid-soluble or water-soluble), and in a selected way (orally, intravenously, intramuscularly, etc.), the pharmaceutical is designed such that the substance according to a selected release profile (the amount of the active substance released in the organism as a function of time), and/or additional active substances are administered as xe2x80x9cregulating substancesxe2x80x9d which regulating substances act on the organism in the sense of an advantageous control of the pharmacokinetics of the pharmacologically active substance.
Particularly for pharmaceuticals which are orally administered, a plurality of methods are known in order to generate for the pharmacologically active substances contained in the pharmaceutical freely selectable release profiles within wide limits. Such release profiles comprise, for example, a delayed release (for example, according to U.S. Pat. No. 5,788,987), a release as uniformly as possible over a time period as long as possible or a pulsatile release over an extended period of time (for example, according to U.S. Pat. No. 5,229,131). Moreover, administration forms are known in which two or more release types are combined to a release profile such that, for example, of a pharmacologically active substance a first portion is immediately released (burst) and the residual amount is distributed over a longer period of time (for example, according to U.S. Pat. Nos. 5,879,710, 5,738,874, or 5,407,686) or that, after a uniform release over a certain period of time, a release burst takes place (according to U.S. Pat. No. 5,213,808). It has also been proposed to administer the pharmacologically active substance in the form of a plurality of particles, wherein particles, which are designed for different release times, can be combined to a mixture with a substantially freely selectable release profile (for example, according to U.S. Pat. No. 5,840,329).
It is also known to employ administration forms in which different release types are combined with one another for the combined administration of more than one pharmacologically active substance wherein, for example, a first one of the substances is designed to provide a desired pharmacological activity and wherein a further one of the substances is administered for regulating the pharmacokinetics of the first substance. The administration of a substance (for example, benserazide or carbidopa), which is administered in combination with L-dopa against Parkinson""s disease and which is released before L-dopa, as described, for example, in U.S. Pat. No. 5,738,874, is to be understood in this way. The regulating substance delays the metabolism of L-dopa to dopamine and ensures that a quantity as large as possible of the administered amount reaches in the form of unchanged L-dopa the blood-brain interface which it can pass only in this unchanged form. In a similar way, substances for inhibiting or ameliorating the undesirable side effects of a first active substance are released as, for example, the release of a substance, described in the same publication, for inhibiting irritation of the mucous membranes of the gastro-intestinal tract before the release of a pharmacologically active substance which irritates these mucous membranes as an undesirable side effect.
With the above addressed pharmaceuticals it is thus attempted, in particular, via the release profile and via the pharmacokinetics, to adapt the activity profile of a pharmacologically active substance to specific requirements, wherein, however, a plurality of parameters which determine such an activity profile, in particular, such parameters which are coupled with one another, may remain unaffected.
DE 43 25 465 describes a pharmaceutical allowing release of an opioid antagonist before an opioid agonist. The former shall overcome the paralytic effects of the opioid on peristaltic motion of the gut leading to constipation, while the therapeutic effect of the opioid agonist is not negatively affected. GB 791 644 describes the timely staggered use of glutarimide in a pharmaceutical in combination with barbiturates in order to overcome toxic effects of barbiturate overdosing. In both cases, the drugs to be released at different time points are combined such that the negative and undesirable effects of an active compound (paralysis of peristaltic motion, toxicity) are diminished while the desired activity remains intact.. On the other hand, U.S. Pat. No. 3,287,220 describes the increase in activity of a drug cocktail against asthma by a protease that is encapsulated in the core of a solid pharmaceutical also comprising the members of the drug cocktail. FR 25 84 604 describes the use of combinations of two pharmaceuticals, especially analgetics, A and B where one of these components is integrated such into a pharmaceutical that it is released fast, the other in a retarded way, so that the (analgetic) activity starts fast due to the fast release of the first component and lasts longer due to slower release of the second. Finally, FR 23 46 087 describes the combination of a soporific drug and a blood pressure stabilizing/circulation enhancing drug that is released some time after the soporific drug in order to maintain sleep in elder people by avoiding their awakening due to a critical lowering of blood pressure that occurs late in the night. In all these cases, the combinations are intended to support or enhance the effect of a drug on the same biologic phenomenon (antiasthmatic effect, pain reduction or sleep, respectively) by another compound in the same direction.
None of these references that always deal with synergistic combinations or combinations where one of the combination partners just has the task to compensate for an undesired effect of the other partners suggests or in any way supports the idea of the present invention:
The invention has the object to provide a pharmaceutical with which it is possible to design, as desired, flank phases of the activity profile (phases in which the activity intensity increases or decreases significantly) of a pharmacologically active substance, in particular, end flank phases with decreasing activity or, in a different aspect of the invention, initial flank phases with increasing activity intensity, without, however, affecting other phases of the activity profile and without reducing the design freedom for such other phases.
The invention relates to a pharmaceutical comprising (i) a first pharmacologically active substance, which acts on a specific biological function, which substance is integrated such into the pharmaceutical that it is released according to a predetermined first release profile (D.1), which generates a first activity profile (I.1) with at least one flank of increasing and at least one flank of decreasing activity intensity, and (ii) for changing at least one flank phase of the first activity profile (I.1) an additional pharmacologically active substance having activity on the same biological function in a modifying way and which is integrated such that it is released according to a second release profile (D.2, D.3) which generates a second activity profile (I.2, I.3), wherein the second activity profile (I.2, I.3) overlaps the flank phase of the first activity profile (I.1) to be changed; with the proviso that where the term substance is used this refers to the respective compound and/or a pharmaceutically acceptable salt thereof (reference signs refer to FIGS. 1-3).
The resulting modification of the effect of said first pharmacologically active substance by said additional pharmacologically active substance is an approach that is totally different from the prior art combinations.
The preferred pharmaceutical according to the invention is thus based on the principle of affecting in a desired way flank phases of the activity profile of a first pharmacologically active substance, whose activity relates to a specific biological function, by over-laying it with at least one other activity profile of an additional pharmacologically active substance acting on the same biological function in a modifying way, preferably in a way antagonizing the effect on the same biological function of said first pharmacologically active substance.
In other terms, for shortening the phase of a decreasing end flank of the activity profile of a first pharmacologically active substance, a second substance is therefore used which has an antagonizing action on the same biological function as the action of the first substance and which is released such that its activity profile overlaps the activity profile of the first substance in the end flank phase. This provides an activity combination in which the two oppositely directed activities overcome one another at least partially.
Applications for this administration form of the pharmaceutical according to the invention can be found, in particular, where temporally sharply limited activities of relatively high intensity are required or desired, i.e., where an underlying xe2x80x9cafter-effectxe2x80x9d of a pharmacologically active substance is to be suppressed. This is, for example, the case for soporific agents whose activity, in particular, in high dosages with an uncomfortably long end phase is not sufficient for sleeping and is not beneficial for the waking state. This end phase of the activity of an active substance is significantly shortened according to the invention by the counteracting substance, in the case of a soporific agent by a stimulating agent or dopant which is released for its activity in the end flank phase.
Conversely, according to a different aspect of the invention, for shortening an ascending initial flank of the activity profile of a first pharmacologically active substance whose activity relates to a specific biological function, a second pharmacologically active substance of same activity is used such that the second activity profile overlaps the flank phase of the first activity profile and accelerates the activity increase in this phase.
For shortening the initial flank phase of an active substance having a strong activity, being side effect-reduced or otherwise advantageous but acting for some reason only with undesirably great delay, it is therefore possible to employ in the initial flank phase a small dosage of a substance of same activity but being less advantageous for some reason, wherein, especially, undesirable side effects of the second substance have no consequence as a result of the temporally very limited and very small dosage.
The combined pharmacologically active substances in the pharmaceutical according to the invention could also be taken or administered separately. However, the combination in a single pharmaceutical has the advantage, on the one hand, of improved patient compliance in the case of a planned pharmacological treatment and, on the other hand, an a priori avoidance of uncomfortable side effects which therefore do not occur at all and which must not be fought deliberately after their occurrence. Accordingly, the acceptance of a pharmacologically active substance can be considerably improved.